Solid state forms of spiro-oxindole compounds

ABSTRACT

The present invention provides solid state forms of certain spiro-oxindole compounds, such as funapide and the racemic mixture of funapide and its corresponding (R) enantiomer, pharmaceutical compositions comprising the solid state forms and processes for preparing the solid state forms and the pharmaceutical compositions.

FIELD OF THE INVENTION

The present invention encompasses solid state forms of certainspiro-oxindole compounds, pharmaceutical compositions comprising thesolid state forms and pharmaceutically acceptable excipients, andprocesses for preparing the solid state forms and the pharmaceuticalcompositions.

BACKGROUND OF THE INVENTION

PCT Published Patent Application No. WO 2006/110917, PCT PublishedPatent Application No. WO 2010/045251, PCT Published Patent ApplicationNo. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174,PCT Published Patent Application No. WO 2011/002708, PCT PublishedPatent Application No. WO 2011/106729 and PCT Published PatentApplication No. WO 2013/154712, discloses certain spiro-oxindolecompounds, methods of preparing the spiro-oxindole compounds,pharmaceutical compositions comprising the spiro-oxindole compoundsand/or methods of using the spiro-oxindole compounds.

One of these spiro-oxindole compounds is funapide, which is also knownas TV-45070 or XEN402. Funapide has the following formula (I-S):

and has the chemical name of(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one.

In particular, PCT Published Patent Application No. WO 2011/002708specifically discloses funapide and its corresponding (R)-enantiomer;PCT Published Patent Application No. WO 2011/047174 discloses methods ofpreparing funapide by resolving its racemate by either SMBchromatography or by chiral HPLC; and PCT Published Patent ApplicationNo. WO 2013/154712 discloses methods of preparing funapide by asymmetricsynthesis.

Funapide is the (S)-enantiomer of the racemic compound previouslydisclosed in PCT Published Patent Application No. WO 2006/110917 ascompound #428 therein. Compound #428 is also known as XEN401.

Funapide and pharmaceutical compositions comprising funapide are usefulfor the treatment of sodium channel-mediated diseases, preferablydiseases related to pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome; neuroprotectionagainst stroke, neural trauma and multiple sclerosis; andchannelopathies such as erythromelalgia and familial rectal painsyndrome.

The relevant disclosures of the above published patent applications areincorporated in full by reference herein.

Polymorphism, the occurrence of different crystalline forms of the samemolecule, is a property of some molecules and molecular complexes. Asingle molecule may give rise to a variety of polymorphs having distinctcrystal structures and physical properties such as melting point,thermal behaviors (e.g., measured by differential scanningcalorimetry—“DSC” or thermogravimetric analysis—“TGA”), X-raydiffraction pattern, infrared absorption fingerprint, and solid state(¹³C—) NMR spectrum. One or more of these techniques may be used todistinguish different polymorphic forms of a compound.

Different solid state forms (including solvated forms) of an activepharmaceutical ingredient may possess different properties. Suchvariations in the properties of different solid state forms and solvatesmay provide a basis for improving formulation, for example, byfacilitating better processing or handling characteristics, changing thedissolution profile in a favorable direction, or improving stability(polymorphic as well as chemical stability) and shelf-life. Thesevariations in the properties of different solid state forms may alsooffer improvements to the final dosage form, for instance, if they serveto improve bioavailability. Different solid state forms and solvates ofan active pharmaceutical ingredient may also give rise to a variety ofpolymorphs or crystalline forms, which may in turn provide additionalopportunities to assess variations in the properties and characteristicsof a solid active pharmaceutical ingredient.

Discovering new solid state forms and solvates of a pharmaceuticalproduct may yield materials having desirable processing properties, suchas ease of handling, ease of processing, storage stability, and ease ofpurification or as desirable intermediate crystal forms that facilitateconversion to other polymorphic forms. New solid state forms of apharmaceutically useful compound can also provide an opportunity toimprove the performance characteristics of a pharmaceutical product. Itenlarges the repertoire of materials that a formulation scientist hasavailable for formulation optimization, for example by providing aproduct with different properties, e.g., a different crystal habit,higher crystallinity or polymorphic stability which may offer betterprocessing or handling characteristics, improved dissolution profile, orimproved shelf-life (chemical/physical stability). For at least thesereasons, there is a need for solid state forms (including solvatedforms) of funapide.

SUMMARY OF THE INVENTION

The present invention provides solid state forms of certainspiro-oxindole compounds, preferably funapide or the racemic mixture, asdisclosed herein, and pharmaceutical compositions thereof.

The present invention also encompasses the use of any one of solid stateforms of certain spiro-oxindole compounds, preferably funapide or theracemic mixture, as disclosed herein, for the preparation ofpharmaceutical compositions of the spiro-oxindole compounds.

The present invention also provides methods of preparing the solid stateforms of certain spiro-oxindole compounds, preferably funapide or theracemic mixture, as disclosed herein.

The present invention also provides a process for preparing theabove-mentioned pharmaceutical compositions. The process comprisescombining any one of the solid state forms of certain spiro-oxindolecompounds, preferably funapide or the racemic mixture, as disclosedherein, with at least one pharmaceutically acceptable excipient.

The solid state forms and the pharmaceutical compositions of certainspiro-oxindole compounds, preferably funapide or the racemic mixture,can be used as medicaments, particularly for the treatment of sodiumchannel-mediated diseases and conditions, such as pain.

The present invention also provides a method of treating sodiumchannel-mediated diseases and conditions, such as pain, comprisingadministering a therapeutically effective amount of any one of the solidstate forms of certain spiro-oxindole compounds, preferably funapide orthe racemic mixture, as disclosed herein, or at least one of the abovepharmaceutical compositions, to a subject suffering from sodiumchannel-mediated diseases and conditions, such as pain, or otherwise inneed of the treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a characteristic X-ray powder diffractogram of Form A₀ offunapide (TV-45070).

FIG. 2 shows a DSC thermograph of Form A₀ of funapide (XEN-402).

FIG. 3 shows an FTIR spectrum by ATR of Form A₀ of funapide.

FIG. 4 shows a Raman shift spectrum for Form A₀ of funapide.

FIG. 5 shows a characteristic X-ray powder diffractogram of Form B₀ offunapide (TV-45070).

FIG. 6 shows a DSC thermograph of Form B₀ of funapide (TV-45070).

FIG. 7 shows an FTIR spectrum by ATR of Form B₀ of funapide.

FIG. 8 shows a Raman shift spectrum for Form B₀ of funapide.

FIG. 9 shows a characteristic X-ray powder diffractogram of amorphousfunapide (TV-45070).

FIG. 10 shows a DSC thermograph of the amorphous form of funapide(TV-45070).

FIG. 11 shows a characteristic X-ray powder diffractogram of the racemicmixture of funapide and its corresponding (R)-enantiomer.

FIG. 12 shows a Raman shift spectrum for the racemic mixture of funapideand its corresponding (R)-enantiomer.

FIG. 13 shows an overlay of the X-ray powder diffractograms of theracemic mixture, Form A₀ of funapide and Form B₀ of funapide.

FIG. 14 shows an overlay of the Raman shift spectrums of the racemicmixture, Form A₀ and Form B₀.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses solid state forms of certainspiro-oxindole compounds, preferably funapide or a racemic mixture offunapide and its corresponding (R)-enantiomer. Solid state properties offunapide or the racemic mixture can be influenced by controlling theconditions under which funapide or the racemic mixture is obtained insolid form.

As used herein, “solid state forms of certain spiro-oxindole compounds”is intended to include the crystalline forms of funapide, the amorphousform of funapide, and the crystalline form of the racemic mixturecomprising funapide and its corresponding (R)-enantiomer, as describedherein.

In some embodiments, the crystalline forms of funapide of the inventionare substantially free of any other forms of funapide, or of specifiedpolymorphic forms of funapide, respectively.

As used herein, “substantially free” when referring to a solid stateform of the funapide is intended to mean that the solid state form ofthe present invention contains 20% (w/w) or less of any otherpolymorphs, or of specified polymorph of funapide, or the amorphous formof funapide. According to some embodiments, a solid state form offunapide contains 10% (w/w) or less, 5% (w/w) or less, 2% (w/w) or less,1% (w/w) or less, 0.5% (w/w) or less, or 0.2% (w/w) or less of any otherpolymorphs, or of specified polymorph of funapide or the amorphous formof funapide. In other embodiments, a solid state form of funapide of thepresent invention contains from 1% to 20% (w/w), from 5% to 20% (w/w),or from 5% to 10% (w/w) of any other solid state form or of a specifiedpolymorph of funapide or of the amorphous form of funapide.

Depending on with which other solid state form a comparison is made, thecrystalline forms of funapide of the present invention have advantageousproperties selected from at least one of the following: chemical purity,flowability, solubility, dissolution rate, morphology or crystal habit,stability—such as chemical stability as well as thermal and mechanicalstability with respect to polymorphic conversion, stability towardsdehydration and/or storage stability, low content of residual solvent, alower degree of hygroscopicity, flowability, and advantageous processingand handling characteristics such as compressibility, and bulk density.

Particularly, it has been found that the crystalline forms of funapideof the present invention are highly soluble in numerous solvents such asacetone, acetonitrile, ethyl acetate, isopropyl acetate, methyltert-butyl ether, tetrahydrofuran and toluene. The crystalline forms offunapide of the present invention also demonstrate good physicalstability.

As used herein, the term “highly soluble” in reference to solid stateforms of funapide of the present invention corresponds to a solid stateform of funapide having a solubility of above 100 mg/mL at roomtemperature.

A solid state form, such as a crystalline form or an amorphous form, maybe referred to herein as being characterized by graphical data “asdepicted in” or “as substantially depicted in” a Figure. Such datainclude, for example, powder X-ray diffractograms, DSC thermographs,FTIR spectrums by ATR and Raman shift spectrums. As is well-known in theart, the graphical data potentially provides additional technicalinformation to further define the respective solid state form (aso-called “fingerprint”) which cannot necessarily be described byreference to numerical values or peak positions alone. In any event, theskilled person will understand that such graphical representations ofdata may be subject to small variations, e.g., in peak relativeintensities and peak positions due to certain factors such as, but notlimited to, variations in instrument response and variations in sampleconcentration and purity, which are well known to the skilled person.Nonetheless, the skilled person would readily be capable of comparingthe graphical data in the Figures herein with graphical data generatedfor an unknown crystalline form and confirm whether the two sets ofgraphical data are characterizing the same crystal form or two differentcrystal forms. A crystalline form of funapide or the racemic mixturereferred to herein as being characterized by graphical data “as depictedin” or “as substantially depicted in” a Figure will thus be understoodto include any crystalline forms of funapide or the racemic mixturecharacterized with the graphical data having such small variations, asare well known to the skilled person, in comparison with the Figure.

As used herein, the term “isolated” in reference to solid state forms offunapide or the racemic mixture of the present invention corresponds toa solid state form of funapide or the racemic mixture that is physicallyseparated from the reaction mixture in which it is formed.

As used herein, unless stated otherwise, the XRPD measurements are takenusing copper Kα radiation at 45 kV and 40 mA.

As used herein, unless stated otherwise, the DSC measurements weremeasured with a heat ramp of 10° C./min.

When an object or a mixture, such as a solid state form of funapide orthe racemic mixture or a reaction mixture or solution, is characterizedherein as being at or allowed to come to “room temperature” or “ambienttemperature” (often abbreviated as “RT”), it is intended to mean thatthe temperature of the object or mixture is close to, or the same as,that of the space, e.g., the room or fume hood, in which the object ormixture is located. Typically, room temperature is from about 20° C. toabout 30° C., or about 22° C. to about 27° C., or about 25° C.

The amount of solvent employed in a chemical process, e.g., a reactionor a crystallization, may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending a5 grams of a material in 10 volumes of a solvent means that the solventis used in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding solvent X (1.5 v/v)to a 100 ml reaction mixture would indicate that 150 mL of solvent X wasadded.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, or about 10-18 hours, typically about 16 hours. As usedherein, the term “reduced pressure” refers to a pressure that is lessthan atmospheric pressure. For example, reduced pressure is about 10mbar to about 50 mbar.

As used herein “crystalline form A₀ of funapide” or “Form A₀” or “FormA₀ of funapide” refers to a crystalline form of funapide which may becharacterized by X-ray powder diffraction pattern as depicted in FIG. 1.

As used herein “crystalline form B₀ of funapide” or “Form B₀” or “FormB₀ of funapide” refers to a crystalline form of funapide which may becharacterized by X-ray powder diffraction pattern as depicted in FIG. 5.

As used herein “amorphous form of funapide” refers to an amorphous formof funapide which may be characterized by X-ray powder diffractionpattern as depicted in FIG. 9 and further by a DSC thermograph asdepicted in FIG. 10 showing a glass transition at 42° C. andcrystallization at 72° C.

As used herein “the racemic mixture” refers to the crystalline form ofthe racemic mixture of funapide and its corresponding (R)-enantiomerwhich may be characterized by an X-ray powder diffraction pattern asdepicted in FIG. 11.

In one embodiment, the present invention comprises a crystalline form offunapide, designated herein as crystalline form A₀ of funapide,characterized by data selected from one or more of the following: X-raypowder diffraction pattern having peaks at 10.10°, 10.69°, 20.59°,22.69° and 33.12° θ±0.2° θ; an X-ray powder diffraction pattern asdepicted in FIG. 1; and combinations of these data.

Crystalline form A₀ of funapide may be further characterized by theX-ray powder diffraction pattern having peaks at 10.10°, 10.69°, 20.59°,22.69° and 33.12° θ±0.2° θ and also having one, two, three or fouradditional peaks selected from: 15.94°, 17.77°, 20.26°, 23.79°, and30.84° θ±0.2° θ; a DSC thermogram as depicted in FIG. 2; a 110-116° C.melting point, preferably a 114-116° C. melting point; an FTIR spectrumas depicted in FIG. 3, and a Raman shift spectrum as depicted in FIG. 4.

Crystalline form A₀ of funapide may be characterized by each of theabove characteristics alone and/or by all possible combinations, e.g.,by X-ray powder diffraction pattern having peaks at 10.10°, 10.69°,20.59°, 22.69° and 33.12° θ±0.2° θ and by an X-ray powder diffractionpattern as depicted in FIG. 1.

In another embodiment, crystalline form A₀ of funapide is characterizedby one or more of the following Raman shift peaks listed in Table 1:

TABLE 1 Peak No. Raman shift (cm⁻¹) 1 3137.83 2 3110.35 3 3088.66 43075.64 5 3062.62 6 3012 7 2973.91 8 2938.23 9 2890.5 10 2880.85 112846.14 12 2773.34 13 1718.42 14 1632.6 15 1608.98 16 1601.75 17 1554.518 1502.43 19 1489.89 20 1468.19 21 1451.8 22 1429.62 23 1394.43 241379.96 25 1374.66 26 1345.25 27 1338.02 28 1302.34 29 1280.64 301260.88 31 1234.36 32 1216.04 33 1203.98 34 1169.27 35 1162.04 361104.18 37 1018.36 38 968.7 39 937.84 40 823.1 41 776.81 42 761.86 43751.26 44 740.17 45 706.9 46 679.9 47 646.15 48 626.38 49 567.08 50494.76 51 490.9 52 453.78 53 428.71 54 406.53 55 386.76 56 375.19 57312.03 58 300.94 59 276.84 60 228.62 61 189.09 62 142.32 63 116.28 6481.57 65 60.84

In another embodiment, the present invention comprises crystalline formof funapide, designated herein as crystalline form B₀ of funapide,characterized by data selected from one or more of the following: X-raypowder diffraction pattern having peaks at 9.61°, 10.03°, 14.95°,19.28°, and 21.30° θ±0.2° θ; an X-ray powder diffraction pattern asdepicted in FIG. 5; and combinations of these data.

Crystalline form B₀ of funapide may be further characterized by theX-ray powder diffraction pattern having peaks at 9.61°, 10.03°, 14.95°,19.28°, and 21.30° θ±0.2° θ and also having one, two, three or fouradditional peaks selected from: 12.51°, 16.14°, 18.03°, 18.72°, and25.50° θ±0.2° θ; a DSC thermogram as depicted in FIG. 6 showing a104-107° C. melting point; an FTIR spectrum as depicted in FIG. 7 and aRaman shift spectrum as depicted in FIG. 8.

Crystalline form B₀ of funapide may be characterized by each of theabove characteristics alone and/or by all possible combinations, e.g. byX-ray powder diffraction pattern as having peaks at 9.61°, 10.03°,14.95°, 19.28°, and 21.30° θ±0.2° θ and by an X-ray powder diffractionpattern as depicted in FIG. 5.

In another embodiment, crystalline form B₀ of funapide is characterizedby one or more of the following Raman shift peaks listed in Table 2:

TABLE 2 Peak No. Raman shift (cm⁻¹) 1 3136.39 2 3121.92 3 3108.9 43090.1 5 3069.37 6 3029.35 7 3010.07 8 2981.14 9 2966.19 10 2957.51 112932.92 12 2905.93 13 2891.46 14 2849.03 15 2785.39 16 1727.1 17 1715.0518 1635.98 19 1612.35 20 1601.75 21 1569.44 22 1501.46 23 1490.37 241467.71 25 1433 26 1390.09 27 1376.11 28 1346.21 29 1339.46 30 1321.1431 1303.3 32 1278.23 33 1247.86 34 1212.66 35 1178.43 36 1157.7 371100.32 38 1043.91 39 1018.36 40 957.61 41 937.36 42 825.51 43 799.95 44758.01 45 744.99 46 734.86 47 726.19 48 718.95 49 704.01 50 685.69 51674.12 52 634.58 53 581.55 54 569.49 55 493.8 56 488.01 57 432.08 58394.96 59 372.78 60 327.94 61 322.16 62 300.46 63 282.14 64 257.55 65224.28 66 210.3 67 202.1 68 164.98 69 124.96 70 112.43 71 90.73 72 61.8

In one embodiment, the present invention comprises a crystalline form ofthe racemic mixture of funapide and its corresponding (R)-enantiomer,designated herein as the crystalline form of the racemic mixture,characterized by data selected from one or more of the following: X-raypowder diffraction pattern having peaks at 13.68°, 14.83°, 20.17°,25.49° and 29.80° θ±0.2° θ; an X-ray powder diffraction pattern asdepicted in FIG. 11; and combinations of these data.

The crystalline form of the racemic mixture may be further characterizedby the X-ray powder diffraction pattern having peaks at 13.68°, 14.83°,20.17°, 25.49° and 29.80° θ±0.2° θ and also having one, two, three orfour additional peaks selected from: 15.94°, 22.24°, 27.21°, and 31.91°θ±0.2° θ; and a Raman shift spectrum as depicted in FIG. 12.

In another embodiment, the racemic mixture is characterized by one ormore of the XRPD peaks listed in Table 3:

TABLE 3 Pos. [°2θ] d-spacing [Å] Rel. Int. [%] 12.38 7.15 3 13.68 6.4717 14.83 5.97 100 15.94 5.56 5 17.74 5.00 3 18.98 4.67 2 20.17 4.40 621.78 4.08 4 22.24 3.99 4 25.07 3.55 3 25.11 3.54 3 25.49 3.49 6 27.213.27 5 27.45 3.25 3 29.13 3.06 2 29.58 3.02 1 29.80 3.00 8 31.54 2.83 231.91 2.80 4 39.12 2.30 3

In another embodiment, the crystalline form of the racemic mixture ischaracterized by one or more of the following Raman shift peaks listedin Table 4:

TABLE 4 Peak No. Raman shift (cm⁻¹) 1 3147.48 2 3113.73 3 3093.48 43075.64 5 3060.69 6 3013.92 7 2984.03 8 2955.1 9 2931.48 10 2909.3 112848.07 12 2715.96 13 1717.94 14 1611.87 15 1602.71 16 1569.93 171505.32 18 1487 19 1469.64 20 1430.11 21 1375.14 22 1350.55 23 1308.6124 1279.68 25 1259.91 26 1226.16 27 1197.72 28 1159.14 29 1105.63 301012.09 31 969.18 32 938.33 33 822.13 34 778.74 35 759.45 36 749.33 37741.61 38 720.4 39 714.61 40 695.33 41 684.24 42 619.63 43 604.69 44495.73 45 488.01 46 454.74 47 431.12 48 422.92 49 413.76 50 393.03 51369.41 52 350.12 53 323.12 54 299.01 55 270.57 56 240.19 57 205.96 58160.16 59 133.64 60 114.84 61 82.53 62 78.68 63 70.48 64 54.57

The present invention comprises pharmaceutical compositions andformulations comprising any one of the crystalline forms of funapide,the amorphous form of funapide or the crystalline form of the racemicmixture of the present invention and one or more pharmaceuticallyacceptable excipients. Typically, the pharmaceutical composition is asolid composition and the funapide retains its solid state form therein.

The pharmaceutical compositions of the invention can be prepared bymethods similar to those disclosed in PCT Published Patent ApplicationWO 2011/047174 or by methods similar to those disclosed in PCT PublishedPatent Application No. WO 2013/154712 or by methods similar to thosedisclosed in PCT Published Patent Application No. WO 2011/106729.

The above crystalline forms of funapide and the racemic mixture and theamorphous form of funapide of the present invention can also be used asa medicament.

The present invention further encompasses 1) the use of theabove-described crystalline forms or amorphous form of funapide or thecrystalline form of the racemic mixture in the manufacture of apharmaceutical composition, and 2) a method of treating a subjectsuffering from sodium channel-mediated diseases and conditions, such aspain, or otherwise in need of the treatment, comprising administrationof an effective amount of a pharmaceutical composition comprising anyone of the above crystalline forms or amorphous form of funapidedescribed herein.

The use of the above crystalline forms or amorphous form of funapide orthe crystalline form of the racemic mixture and pharmaceuticalcompositions comprising same can be used in treating the diseases andconditions as described in PCT Published Patent Application No. WO2011/002708.

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to limit its scope in any way.

The funapide used herein to prepare the crystalline forms of funapidedisclosed herein was prepared according to the methods disclosed in PCTPublished Patent Application No. WO 2011/047174 and/or by the methodsdisclosed in PCT Published Patent Application No. WO 2013/154712.

Analysis Methods

XRPD—X-Ray Powder Diffraction

X-ray powder diffraction (XRPD, also known as powder X-ray diffractionor powder XRD) patterns were recorded on a PANalytical X'Pert Prodiffractometer equipped with an X′celerator detector using Cu Kαradiation at 45 kV and 40 mA. The diffractometer was controlled withPANalytical Data Collector1. All samples were analyzed using algorithmsin HighScorePlus2.

Standard Reflection Mode

Kα1 radiation was obtained with a highly oriented crystal (Ge111)incident beam monochromator. A 10 mm beam mask, and fixed)(¼° divergenceand anti-scatter)(⅛° slits were inserted on the incident beam side. A0.04 radian Soller slits and a fixed 5 mm receiving slit were insertedon the diffracted beam side. The X-ray powder pattern scan was collectedfrom ca. 2 to 40° 2θ with a 0.0080° step size and 96.06 sec countingtime which resulted in a scan rate of approximately 0.5°/min. The samplewas spread on a silicon zero background (ZBG) plate for the measurement.The sample was rotated at 15 revolutions/min on a PANalytical PW3065/12Spinner. Measurement of the Si reference standard before the datacollection resulted in values for 2θ and intensity that were well withinthe tolerances of 28.0°<2θ<28.5° and significantly greater than theminimum peak height of 150 cps.

Capillary Transmission Mode

Powder XRD patterns were recorded on a PANalytical X Pert Prodiffractometer equipped with an X celerator detector using Cu Kαradiation at 45 kV and 40 mA. An incident beam (Cu W/Si) focusing MPDmirror was used in the incident beam path. Fixed ( 1/20) divergence andanti-scatter ( 1/40) slits and 0.01 Sollers were inserted on theincident beam side. A fixed 5.0 mm antiscatter slit and 0.01 Sollerswere inserted on the diffracted beam side. If the antiscatter device(PW3094/10) is employed, an additional 2.0 mm slit is positioned 197 mmfrom the detector. The X-ray powder pattern scan was collected from ca.2.75 to 40° 2θ with a 0.0080° step size and 101 second counting timewhich resulted in a scan rate of approximately 0.5°/min. The sample wasloaded into a thin walled Kapton capillary and place in a modifiedtransmission holder. The holder is a standard transmission sample ringwith added mechanical features that allow for measurement of a spinningcapillary.

Variable Temperature (VT) Mode

Variable temperature studies were preformed with an Anton Paar CHCtemperature/humidity chamber under computer control. The temperatureswere set with Data Collector using an Anton Paar TCU110 temperaturecontrol unit.

Kα radiation was obtained with a Nickel filter. A fixed ( 1/40)divergence and anti-scatter ( 1/20) slits were inserted on the incidentbeam side. A fixed 0.10 mm receiving slit was inserted on the diffractedbeam side. Soller slits (0.04 radians) were inserted in both theincident and diffracted beam sides. The X-ray powder pattern scan wascollected from ca. 2 to 40° 2θ with a 0.0080° step size and 96.06 seccounting time which resulted in a scan rate of approximately 0.5°/min.

For temperature studies, measurements were made with N₂ gas flow. Thetemperatures chosen for study were based on DSC results. Measurementswere started after the CHC chamber reached requested temperature. Afterthe requested temperature was reached, the sample was cooled at 35°C./minute and a slow scan was measured at 25° C. This technique avoids“cooking” the sample at higher temperatures. Scans were collected fromca. 3° to 30° or 40° 2θ with a 0.008° step size and 100 sec countingtime which resulted in a scan rate of approximately 0.5°/min.

DSC—Differential Scanning Calorimetry

Thermal curves were acquired using a Perkin-Elmer Sapphire DSC unitequipped with an autosampler running Pyris software version 6.0calibrated with Indium prior to analysis. Solid samples of 1-10 mg wereweighed into 20 μL aluminum pin hole sample pans. The DSC cell was thenpurged with nitrogen and the temperature heated from 0 to 270° C. at 10°C./min. Indium (Tm=156.6° C.; ΔHFus=28.45 J/g) was used for calibration.

FTIR Spectroscopy

Spectra were obtained using a Bruker Tensor 27 with ATR attachmentcontaining a diamond crystal window. The OPUS data collection program(Version 7.0, Bruker) was used to obtain the IR spectrum from 4000 to400 cm⁻¹. A background scan was collected before spectral resolution andaveraged.

Raman Spectroscopy

Raman spectra were collected on a Vertex 70 FTIR (Bruker) optical benchequipped with a 1064 nm NdYAG laser and liquid-nitrogen cooled Gedetector with either the RAMII module or the RamanScope. Thirty-twoscans were collected in a double-sided acquisition mode at 5 KHz scanvelocity with a 5 mm aperture. Data was processed with a phaseresolution of 32 cm⁻¹, 8× zero-filling and a weak Norton-Beerapodization function. Sample spectra were collected through the glassvial using the RAMII whenever possible. Irregularly shaped samples wereanalyzed on the RamanScope using a 10×. In that situation, 64 scans werecollected with an 1197 mW laser power.

Screening Methods

Slurry Equilibration in Different Solvents

Equilibration at 25° C.

Approximately 20 mg of funapide was equilibrated with ˜0.2 mL solventsfor at least 48 h at 25±3° C. in 4 mL vials. The resulting mixtures werefiltered and the solids air-dried for at least 10 min.

Equilibration at 50° C.

Approximately 40 mg of funapide was equilibrated with ˜0.4 mL solventsfor at least 24 h at 50° C. in 4 mL vials. The solutions were thenfiltered and air-dried for at least 10 min.

Cooling Crystallization at 5° C.

Approximately 20 mg of funapide was completely dissolved in 200 μL ofsolvents at 22-25° C. in 4 mL vials. Care was taken to ensure that therewere no visible crystals remaining. The solutions were cooled to 5° C.at a rate of 2° C./min. The precipitates (if present) were collected ona filter and dried.

Evaporation

Slow Evaporation at 5° C.

Approximately 20 mg of funapide were completely dissolved in 200 μL ofsolvents at 22-25° C. in 4 mL vials. The solutions were cooled to 5° C.at a rate of 2° C./min. Care was taken to ensure there were no visiblecrystals remaining. While temperature and agitation were maintained, thecover of each vial was loosened to allow slow evaporation of the solventfor at least one day.

Fast Evaporation at 50° C.

Approximately 40 mg of funapide were mixed with 200 μL of solvents at22-25° C. in 4 mL vials. The solutions were heated to 50° C. as fast asthe instrument allowed. Care was taken to ensure there were no visiblecrystals remaining at this point. With temperature and agitationmaintained, each vial was uncovered to allow fast evaporation of thesolvent until dryness.

Precipitation by Addition of Anti-Solvent

In 4 mL vials, approximately 20 mg of funapide were completely dissolvedin solvents where funapide solubility is high, and then a secondsolvent, in which funapide is highly insoluble, was added. Samples werewithdrawn from the resulting slurry. The samples were filtered to obtainsolids.

Examples 1-66

The following Examples 1-66 are the solid state forms of funapideresulting from screening with the different methods described above invarying solvents.

TABLE 5 Equilibration at 25° C. (Examples 1-18) Example Solvent XRPD 1Chloroform/2-propanol (1:3) A₀ 2 1,4-dioxane/water (1:3) A₀ 3 Ethylacetate/2-propanol (1:3) A₀ 4 2-propanol B₀ 5 Acetone/water (1:1 v:v) B₀6 Acetic Acid/water (1:1) B₀ 7 Chloroform/heptanes (1:3) B₀ 8Dichloromethane/heptanes (1:3) B₀ 9 Dichloromethane/2-propanol (1:3) B₀10 Ethyl acetate/heptanes (1:3) B₀ 11 Isobutyl alcohol/heptanes (1:3) B₀12 Isopropyl acetate/heptanes (1:3) B₀ 13 Methyl tert-butylether/heptanes (1:3) B₀ 14 Tetrahydrofuran/heptanes (1:3) B₀ 15Toluene/heptanes (1:3) B₀ 16 N-butyl acetate/heptanes (1:1) A₀ + B₀ 17N-butyl acetate/2-propanol (1:3) A₀ + B₀ 18 Heptane A₀ + B₀

TABLE 6 Equilibration at 50° C. (Examples 19-30) Example Solvent XRPD 19Heptanes A₀ 20 Water A₀ 21 Acetic Acid/water (1:1) A₀ 22 Acetone/water(1:1) A₀ 23 n-Butyl acetate/heptanes (1:3) A₀ 24 Chloroform/heptanes(1:3) A₀ 25 Chloroform/2-propanol (1:3) A₀ 26 Ethyl acetate/heptanes(1:3) A₀ 27 Isobutyl alcohol/heptanes (1:3) A₀ 28 Isopropylacetate/heptanes (1:3) A₀ 29 Methyl tert-butyl ether/heptanes (1:3) A₀30 Toluene/heptanes (1:3) A₀

TABLE 7 Cooling Crystallization at 5° C. (Example 31) Example SolventXRPD 31 Methyl tert-butyl ether A₀

TABLE 8 Slow Evaporation at 5° C. (Examples 32-39) Example Solvent XRPD32 Acetone A₀ 33 N-butyl acetate A₀ 34 Ethyl acetate A₀ 35 Isobutylalcohol A₀ 36 Isopropyl acetate A₀ 37 Methyl tert-butyl ether A₀ 38Tetrahydrofuran A₀ 39 Ethyl acetate/heptanes (4:1) A₀

TABLE 9 Fast Evaporation at 50° C. (Examples 40-45) Example Solvent XRPD40 Acetone A₀ 41 Dichloromethane A₀ 42 Isopropyl acetate A₀ 43 Methyltert-butyl ether A₀ 44 Tetrahydrofuran A₀ 45 Toluene A₀

TABLE 10 Anti-Solvent Addition at Room Temperature (Examples 46-66)Example Solvent 1 and solvent 2 XRPD 46 Acetic Acid/water (1:1) A₀ 47Acetone/water (1:1) A₀ 48 n-Butyl acetate/heptanes (1:3) B₀ 49 n-Butylacetate/2-propanol (1:3) A₀ 50 Chloroform/heptanes (1:3) B₀ 51Chloroform/2-propanol (1:3) A₀ 52 Dichloromethane/heptanes (1:3) B₀ 53Dichloromethane/2-propanol (1:3) A₀ 54 1,4-dioxane/water (1:3) B₀ 55Ethyl acetate/heptanes (1:3) B₀ 56 Isobutyl alcohol/heptanes (1:3) B₀ 57Isopropyl acetate/heptanes (1:3) B₀ 58 Tetrahydrofuran/heptanes (1:3) B₀59 Toluene/heptanes (1:3) A₀ 60 Acetic Acid/water (1:1) A₀ 61Acetone/water (1:1) A₀ 62 n-Butyl acetate/heptanes (1:3) B₀ 63 n-Butylacetate/2-propanol (1:3) A₀ 64 Chloroform/heptanes (1:3) B₀ 65Chloroform/2-propanol (1:3) A₀ 66 Dichloromethane/heptanes (1:3) B₀

Example 67 Crystallization Process for Form B₀ of Funapide

Funapide (1.952 Kg) was dissolved in 7070 mL methanol (3.62 volumes).Full dissolution in the 10 L reactor was obtained at 56° C. (inreactor). When the reactor temperature reached 64° C., 742 mL of waterwere added dropwise over a period of 65 minutes. At the end of the wateraddition period a clear solution was still obtained (reactor temperaturereached 68° C.). The solution was mixed for 30 minutes. The jackettemperature was cooled from 85° C. to 40° C. over a period of 40minutes. At the end of this cooling period, temperature in reactorreached 59° C. (jacket temperature was 40° C.) and a white slurry wasobtained. The slurry was cooled according to reactor jacket temperaturefrom 40° C. to −5° C. over a period of 5 hours and mixed for additional11.5 hours. The solid obtained was collected by filtration and washedwith cold mixture of methanol and water (908 mL water and 1160 mLmethanol). The white solid was dried in a vacuum oven at 50° C. for 43hours to obtain a dry solid. Yield: 1831 g (93.8% of theory).

The material was analyzed by XRPD, showing a Form B₀ pattern. The DSC ofthe sample had thermal events at 106.6° C., which is consistent with thetypical Form B₀.

Example 68 Preparation of Amorphous Form of Funapide

A. The amorphous form of funapide was generated by melting Form A₀ offunapide in a dry N₂ atmosphere optionally using the VT stage on theXRPD unit. The sample was heated to 140° C. and then cooled to roomtemperature and crushed. No decomposition was observed. The sample wasconfirmed to be the amorphous form of funapide by XRPD.

B. Alternatively, Form B₀ of funapide may be melted in the same mannerto produce the amorphous form of funapide.

Example 69 Solid State Characterization of Racemic Mixture

A racemic mixture comprising funapide (as Form A₀ of funapide) and itscorresponding (R)-enantiomer was studied to determine if the racemicmixture was a racemic compound or a racemic conglomerate.

FIG. 11 shows a characteristic X-ray powder diffractogram of the racemicmixture. FIG. 12 shows the Raman shift spectrum for the racemic mixture.

FIG. 13 shows an overlay of the X-ray power diffractograms of theracemic mixture, Form A₀ of funapide and Form B₀ of funapide. FIG. 14shows an overlay of the Raman shift spectrum of the racemic mixture,Form A₀ and Form B₀.

The XRPD pattern and melting point of the racemic mixture aredrastically different from that of Form A₀ and Form B₀ (140° C. vs. 110°C. of Form A₀ and 104° C. of Form B₀). Shifts of some Raman peaks of theracemic mixture were also noticeable when compared to those of Form A₀or Form B₀.

To identify the nature of the racemic mixture, a binary phase diagramfrom DSC's of mixtures of the racemic mixture and Form A₀ wasconstructed based on experimental results and theoretical predication. Agood agreement was observed between the experimental results andtheoretical predications. The typical binary phase diagram of a racemiccompound confirmed that the racemic mixture is a racemic compound(instead of a racemic conglomerate).

An overlay of 6 DSC thermographs of the racemic mixture, Form A₀ anddifferent mixtures of the racemic mixture and Form A₀ showed that FormA₀ and the racemic mixture both have one sharp peak which corresponds tothe melting of Form A₀ and the racemic mixture. The mixtures of theracemic mixture and Form A₀, two endothermic peaks; a eutectic fusion(with its onset defined as T_(E)) and a pure species melting (its max asT_(f)) were observed.

The crystal structure of the racemic mixture was resolved. There was onemolecule in the asymmetric unit and there were four pairs of enantiomerspacked in one unit cell. Furthermore, the molecule conformed to the“U-shape” of Form B₀ (rotation along the N—CH₂ bond in funapide giveseither a “Chair-shape”, which conforms with Form A₀, or a “U-shape”,which conforms with Form B₀).

The crystal structure determination of the racemic mixture providesdefinitive evidence that the racemic mixture is a racemic compoundrather than a conglomerate.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

What is claimed is:
 1. A crystalline form of funapide, designated asForm A₀, characterized by one or more of the following: a powder X-raydiffraction pattern having peaks at 10.10°, 10.69°, 20.59°, 22.69° and33.12° θ±0.2° θ; a powder X-ray diffraction pattern substantially asdepicted in FIG. 1; and any combination of these data.
 2. Thecrystalline form of claim 1, characterized by a powder X-ray diffractionpattern having peaks at 10.10°, 10.69°, 20.59°, 22.69° and 33.12° θ±0.2°θ, further characterized by an additional one, two, three, four or fivepowder X-ray diffraction pattern peaks selected from 15.94°, 17.77°,20.26°, 23.79°, and 30.84° θ±0.2° θ.
 3. The crystalline form of funapideaccording to claim 1 or claim 2, further characterized by one or more ofthe following: a DSC thermogram substantially as depicted in FIG. 2; anendothermic onset at 109° C. and a peak max at 114° C., or combinationsthereof.
 4. A pharmaceutical composition comprising the crystalline formof funapide according to claim
 1. 5. A pharmaceutical formulationcomprising the crystalline form of funapide according claim 1 and atleast one pharmaceutically acceptable excipient.
 6. A pharmaceuticalformulation comprising the pharmaceutical composition of claim 4 and atleast one pharmaceutically acceptable excipient.
 7. A method of treatinga subject suffering from sodium channel-mediated diseases andconditions, wherein the method comprises administering to the subject apharmaceutical composition according to claim
 4. 8. A method of treatinga subject suffering from sodium channel-mediated diseases andconditions, wherein the method comprises administering to the subjectthe pharmaceutical formulation according to claim
 5. 9. A method oftreating a subject suffering from sodium channel-mediated diseases andconditions, comprising administering to the subject a therapeuticallyeffective amount of the crystalline form of funapide according toclaim
 1. 10. A method of preparing a pharmaceutical compositioncomprising combining the crystalline form of funapide according to claim1 with a one or more pharmaceutically acceptable excipients.
 11. Amethod of preparing a crystalline form of funapide designated as FormA₀, wherein the method comprises one of the following methods to obtainthe crystalline form of funapide designated as Form A₀: (a)equilibrating funapide at 25±3° C. with a mixture of solvents, filteringthe resulting solutions; and drying the resulting solids; (b)equilibrating funapide at 50° C. with a solvent or mixture of solvents,filtering the resulting solutions and drying the resulting solids; (c)dissolving funapide in methyl tert-butyl ether at 22-25° C., cooling theresulting solution to 5° C., filtering the resulting solution and dryingthe resulting solids; (d) dissolving funapide in a solvent or a mixtureof solvents at 22-25° C., cooling the resulting solutions to 5° C.,maintaining the temperature and allowing the solvent or mixture ofsolvents to slowly evaporate; (e) mixing funapide with a mixture ofsolvents at 22-25° C., rapidly heating the resulting solutions to 50°C., maintaining the temperature and allowing the mixture of solvents torapidly evaporate; and (f) dissolving funapide in a first solvent, inwhich funapide is soluble, adding a second solvent, in which funapide isinsoluble or poorly soluble, and filtering the resulting solutions.